Many blinding eye diseases, such as age-related macular degeneration (AMD) and diabetic retinopathy (DR), are commonly seen in veterans. If left untreated, both AMD and DR can result in irreversible blindness. Both diseases exhibit increased permeability of blood vessels in the macula (central) portion below the retina, the choroid, leading to abnormal fluid accumulation and vision loss. The dry form of AMD does not cause much vision reduction; however, the wet form (10-15% of AMD) is associated with leaky new blood vessels (angiogenesis) and can destroy the central vision. The wet form of AMD is treated with an intravitreal injection of antibodies, a therapy that has transformed eye care. However, intravitreal injections are associated with complications, and patient compliance is poor. Ideally, topical delivery of large molecules to the retina would be preferable, because patients could administer the drug in the comfort of their home. The over-expression of cluster of differentiation 44 (CD44) cell surface receptors is a common feature of many blinding diseases, which offers a fortunate opportunity for research. Overexpression is frequently observed during disease proliferation and inflammation, as well as in cancer growth and metastasis. Retinal pigment epithelial (RPE) cells, as well as the Mller cells and the ganglion cells in the retina, express CD44 receptors in their normal state and overexpress them in disease states. CD44 receptors have an affinity for hyaluronic acid (HA) that enables cells to internalize large molecules that have HA attached to them. Thus, coating drug nanoparticles (NPs) with HA can deliver more drugs to cells that overexpress CD44 receptors and also enable receptor-mediated endocytosis, providing a transcytosis pathway to bypass the ocular barriers. Although any drug-NP can be coated with HA, in this proposal, we will use gold nanoparticles (AuNPs) because their size, shape, and surface properties can be precisely altered. Further, their unique surface plasmon resonance effect can be used for imaging and photothermal therapy, while their anti-angiogenic properties are useful for therapeutic applications. Au-nanorods, in particular, possesses superior photothermal conversion properties. During choroidal neovascularization (CNV), endothelial cells over-express CD44 and release vascular endothelial growth factors, so the innate antiangiogenic activity of AuNPs can be tested. Our strategically designed nanoplatform will enable us to carry various payloads across the barriers and to effectively treat potentially blinding diseases. The proposed research is expected to assess the two routes of administration (for greater specificity, better efficiency, and higher biocompatibility) of our targeted nanoplatform to the retina. This contribution will be significant, because it will both provide a formula for creating a smart biocompatible nano-core-shell carrier and identify a method for effective delivery of drugs to the eye, particularly to the retina. We will synthesize HA-coated au nanorods. Prior to in-vivo applications, we will test the NPs for biocompatibility in tissue culture on retinal pigment epithelial cells. Next, we will assess the efficacy of the Au- nanorods following topical and intravenous administrations in mice that have CNV in the macular region, induced by laser. We will check for retinal toxicity using electroretinography, optical coherence tomography, fluorescein angiography, and histology analysis. The application of HA-NPs can potentially be extended to treating retinal degeneration, choroidal melanoma, retinoblastoma, neovascular glaucoma, and many anterior segment diseases. Our HA-coated AuNP CD44- targeted delivery platform could also be used for cancer theranostics because cancer cells tend to proliferate and need new blood vessel formation for additional oxygen and nutrient supply. If we observe that HA-coated NPs, in addition to crossing the blood-retinal barrier, also cross the blood-brain barrier, we will explore these possibilities with additional collaborators in subsequent studies. Creating a smart nanocarrier can provide an effective treatment strategy, while also reducing treatment costs and increasing patient compliance.